Information Significance of the qSOFA Scale for Current Clinical Medicine. Literature Review

V.A. Rudnov1,2, M.A. Astafeva2

1 Federal State Budgetary Educational Institution of Further Professional Education “Ural state medical university” Ministry of healthcare of the Russian Federation, Yekaterinburg

2 Municipal autonomic health care institution “City Clinical Hospital No. 40”, Yekaterinburg

For correspondence: Rudnov Vladimir Aleksandrovich — Dr. Med. Sci., Professor, Head of the Department of Anesthesiology, Reanimatology and Toxicology, UGMU, Deputy Chief Physician for Anaesthesiology and Reanimatology, MAU GKB No. 40, Ekaterinburg; e-mail: vrudnov@mail.ru

For citation: Rudnov V.A., Astafeva M.A. Information significance of the qSOFA scale for current clinical medicine. Literature review. Alexander Saltanov Intensive Care Herald. 2018;4:30–37.

DOI: 10.21320/1818-474X-2018-4-30-37


Active development of resuscitation and intensive care, establishment of departments and established clinical practice to understand the extreme heterogeneity of patients in critical conditions. One of the tools to reduce the number of errors and make an informed decision, depending on the situation. One of the shortcomings in the consciousness of scoring systems is their relative unwieldiness, the need for mandatory implementation of certain laboratory studies, which requires additional equipment and time. Therefore, attempts were made to create values based on clinical criteria or minimums. To such belongs the “early alarm” scale of the rapid SOFA.

The purpose of this publication was to assess the information significance of the qSOFA scale and determine its role for emergency and critical states, through analysis of literature data.

Conclusion. The qSOFA scale is designed to determine the risk of developing organ-system dysfunction, predicting the outcome of a critical condition and determining the location of the treatment delivery, not inferior to the sensitivity syndrome of the SVR, with respect to the prognosis of the outcome of sepsis in pacities with suspected infection, significantly exceeds its specificity.

Keywords: qSOFA scale, prognosis outcome, lactate, procalcitonin

Received: 19.10.2018


References

  1. Saklad M. Grading of patients for surgical procedures. Anesthesiology. 1941; 2(3): 281–284. DOI: 10.1097/00000542-194105000-00004.
  2. New classification of physical status. Anesthesiology. 1963; 24(1): 111.
  3. Apgar V. A proposal for a new method of evaluation of the newborn infant. Anesthesia and Analgesia. 1953; 32: 260–267. DOI: 10.1213/00000539-195301000-00041.
  4. Knaus W., Zimmerman J., Wagner D., et al. APACHE-acute physiology and chronic health evaluation: a physiologically based classification system. Critical Care Medicine. 1981; 9(8): 591–597. DOI: 10.1097/00003246-198108000-00008.
  5. Knaus W.A., Draper E.A., Wagner D.P., Zimmerman J.E. APACHE II: A severity of disease classification system. Critical Care Medicine. 1985; 13(10): 818–829. DOI: 10.1097/00003246-198510000-00009.
  6. Le Gall J.R., Lemeshow S., Saulnier F. A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. The Journal of the American Medical Association. 1993; 270(24): 2957–2963. DOI: 10.1001/jama.1993.03510240069035.
  7. Fine M.J., Auble T.E., Yealy D.M., et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. New England Journal of Medicine. 1997; 336(4): 243–250. DOI: 10.1056/nejm199701233360402.
  8. Vincent J.L, Moreno R., Takala J., et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Medicine. 1996; 22(7): 707–710. DOI: 10.1007/s001340050156.
  9. Cullen D., Civetta J., Biggs B., Ferrara L.C. Therapeutic intervention scoring system: a method for quantitative comparison of patient care. Critical Care Medicine. 1974; 2(2): 57–60. DOI: 10.1097/00003246-197403000-00001.
  10. Leteurtre S., Duhamel A., Grandbastien B., et al. Paediatric logistic organ dysfunction (PELOD) score. The Lancet. 2006; 367(9514): 897. DOI: 10.1016/s0140-6736(06)68371-2.
  11. Lim W., Van der Eerden M., Laing R., et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003; 58(5): 377–382. DOI: 10.1136/thorax.58.5.377.
  12. Aujesky D., Auble T.E., Yealy D.M., et al. Prospective comparison of three validated prediction rules for prognosis in community-acquired pneumonia. The American Journal of Medicine. 2005; 118(4): 384–392. DOI: 10.1016/j.amjmed.2005.01.006.
  13. Seymour C.W., Liu V.X., Iwashyna T.J., et al. Assessment of clinical criteria for sepsis for the third International consensus definition for sepsis and septic shock (Sepsis-3). The Journal of the American Medical Association. 2016; 315(8): 762–774. DOI: 10.1001/jama.2016.0288.
  14. Churpek M.M., Snyder A., Han X., et al. Quick sepsis-related organ failure assessment, systemic inflammatory response syndrome, and early warning scores for detecting clinical deterioration in infected patients outside the intensive care unit. American Journal of Respiratory and Critical Care Medicine. 2017; 195(7): 906–911. DOI: 10.1164/rccm.201604–0854oc.
  15. Fernando S.M., Reardon P.M., Rochwerg B., et al. Sepsis-3 Septic Shock Criteria and Associated Mortality Among Infected Hospitalized Patients Assessed by a Rapid Response Team. Chest. 2018; 154(2): 309–316. DOI: 10.1016/j.chest.2018.05.004.
  16. Poutsiaka D.D., Porto M., Perry W., et al. Comparison of the Sepsis-2 and Sepsis-3 Definitions of Sepsis and Their Ability to Predict Mortality in a Prospective Intensive Care Unit Cohort. Open Forum Infectious Disease. 2017; 4(Suppl. 1): 602. DOI: 1093/ofid/ofx163.1579.
  17. Park H.K., Kim W.Y., Kim M.C., et al. Quick sequential organ failure assessment compared to systemic inflammatory response syndrome for predicting sepsis in emergency department. Journal of Critical Care. 2017; 42: 12–17. DOI: 10.1016/j.jcrc.2017.06.020.
  18. Battle S.E., Augustine M.R., Bookstaver P.B., et al. A Simplified Pitt Bacteremia Score (qPitt) to Predict Mortality in Patients with Gram-negative Bloodstream Infection. Open Forum Infectious Diseases. 2017; 4(S1): 555–556. DOI: 10.1093/ofid/ofx163.1445.
  19. Burnham J.P., Kollef M.H. qSOFA score: Predictive validity in Enterobacteriaceae bloodstream infections. Journal of critical care. 2018; 43: 143–147. DOI: 10.1016/j.jcrc.2017.09.011.
  20. АстафьеваМ.Н., Руднов В.А., Кулабухов В.В. и др. Использование шкалы qSOFA в прогнозе исхода у пациентов с сепсисом в ОРИТ. Результаты Российского многоцентрового исследования РИСЭС. Вестник анестезиологии и реаниматологии. 2018; 15(5): 26–35. [Astafeva M., Rudnov V., Kulabukhov V., et al. Use of the qSOFA scale in prognosis of outcome of patients with sepsis in ICU. Results of russian national study RISES. Messenger of Anesthesiology and Resuscitation. 2018; 15(5): 26–35. (In Russ)]
  21. Vincent J.L., Rello J., Marshal J., et al. International study of prevalence and outcomes of infection in ICU. The Journal of the American Medical Association. 2009; 302(21): 2323–2329. DOI: 10.1001/jama.2009.1754.
  22. Welte T., Torres A., Nathwani D. Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax. 2012; 67(1): 71–79. DOI: 10.1136/thx.2009.129502.
  23. Chen Y.X., Wang J.W., Guo S.B. Use of CRB-65 and quick Sepsis-related Organ Failure Assessment to predict site of care and mortality in pneumonia patients in the emergency department: a retrospective study. Critical Care. 2016; 20(1): 167. DOI: 10.1186/s13054-016-1351-0.
  24. Ranzani O., Prina E., Menenez R. New Sepsis Definition (Sepsis-3) and Community-acquired Pneumonia Mortality. A Validation and Clinical Decision-Making Study. American Journal of Respiratory and Critical Care Medicine. 2017; 196(10): 1287–1297. DOI: 10.1164/rccm.201611–2262oc.
  25. Kolditz M., Scherag A., Rohde G., et al. Comparison of the qSOFA and CRB-65 for risk prediction in patients with community-acquired pneumonia. Intensive Care Medicine. 2016; 42(12): 2108–2110. DOI: 10.1007/s00134-016-4517-y.
  26. Bhattachajee P., Edelson D., Churpek M. Identifying patients with sepsis on the hospital wards. Chest. 2017; 151(4): 898–907. DOI: 10.1016/j.chest.2016.06.020.
  27. Forward E., Konecny P., Burston J., et al. Predictive validity of the qSOFA criteria for sepsis in non-ICU inpatients. Intensive Care Medicine. 2017; 43: 945–946. DOI: 10.1007/s00134-017-4776-2.
  28. Serafim R., Gomes J.A., Salluh J., Póvoa P. A comparison of the Quick-SOFA and systemic inflammatory response syndrome criteria for the diagnosis of sepsis and prediction of mortality. A systematic review and meta-anallysis. Chest. 2017; 153(3): 646–655. DOI: 10.1016/j.chest.2017.12.015.
  29. Churpek M.M., Snyder A., Sokol S., et al. Investigating the Impact of Different Suspicion of Infection Criteria on the Accuracy of Quick Sepsis-Related Organ Failure Assessment, Systemic Inflammatory Response Syndrome, and Early Warning Scores. Critical Care Medicine. 2017; 45(11): 1805–1812. DOI: 10.1097/ccm.0000000000002648.
  30. Kievlan D., Zhang L.A., Kahn J., et al. Serial evaluation of qSOFA among patients with suspected infection. Critical Care Medicine. 2016; 44(1): 412. DOI: 10.1097/01.ccm.0000510019.33158.70.
  31. Na H.J., Lee K., Jeong E.S., et al. Clinical application of the qSOFA in ICU patients with bacteremia: A single center study in Korea. Critical Care Medicine. 2016; 44(12): 410. DOI: 10.1097/01.ccm.0000510011.79792.02.
  32. Nishiwaki H., Hasegawa T., Sasaki S., et al. External validation study of the qSOFA for Japanese patients undergoing hemodialysis. Nephrology Dialysis Transplantation. 2017; 32(Suppl. 3): 482. DOI: 10.1093/ndt/gfx164.mp148.
  33. АстафьеваМ.Н., Руднов В.А., Кулабухов В.В. и др. Использование шкалы qSOFA в диагностике сепсиса. Вестник анестезиологии и реаниматологии. 2018; 15(4): 14–22. [Astafeva M., Rudnov V., Kulabukhov V., et al. Use of the qSOFA scale in diagnosis of sepsis. Results of russian national study RISES. Messenger of Anesthesiology and Resuscitation. 2018; 15(4): 14–22. (In Russ)]
  34. Kyo M., Ohshimo S., Kida Y., Shime N. The validation qSOFA criteria for sepsis. Critical Care Medicine. 2016; 44(12): 448. DOI: 10.1097/01.ccm.0000510166.80446.5f.
  35. Holdstock V., Shaw M., Puxty A., et al. Ability of qSOFA, SIRS, NEWS, SOFA predict sepsis in patients admitted to ICU. Critical Care Medicine. 2018; 46(1): 740. DOI: 10.1097/01.ccm.0000529515.19526.73.
  36. Schlapbach L.J., Straney L., Bellomo R., et al. Prognostic accurancy of age-adapted SOFA, SIRS, PELOD-2 and qSOFA for in-hospital mortality among children with suspected infection admitted to the intensive care unit. Intensive Care Medicine. 2018; 44(2): 179–188. DOI: 10.1007/s00134-017-5021-8.
  37. Sprung C., Schein R., Balk R. The new consensus definitions: the good, the bad and the ugly. Intensive Care Medicine 2016; 42(12): 2024–2026. DOI: 10.1007/s00134-016-4604-0.
  38. Fantom N., Serajuddin U. The World Bankʼs Classification of Countries by Income, Policy Research Working Paper Series, no. 7528, Washington, DC: World Bank. 2016. [Internet] Available from http://documents.worldbank.org/curated/en/408581467988942234/pdf/WPS7528.pdf (accessed 01.07.2018).
  39. Mills A. Health Care systems in low- and middle-income countries. New England Journal of Medicine. 2014; 370(6): 552–557. DOI: 10.1056/nejmra1110897.
  40. Rudd K.E., Seymour C.W., Aluisio A.R., et al. Association of the Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) Score With Excess Hospital Mortality in Adults With Suspected Infection in Low- and Middle-Income Countries. The Journal of the American Medical Association. 2018; 319(21): 2202–2211. DOI: 10.1001/jama.2018.6229.
  41. Khwannimit B., Bhurayanontachai R., Vattanavanit V. Comparison of the performance of SOFA, qSOFA and SIRS for predicting mortality and organ failure among sepsis patients admitted to the intensive care unit in a middle-income country. Journal of Critical Care. 2018; 44: 156–160. DOI: 10.1016/j.jcrc.2017.10.023.
  42. Ho K.M., Lan N.S.H. Combining quick Sequential Organ Failure Assessment with plasma lactate concentration is comparable to standard Sequential Organ Failure Assessment score in predicting mortality of patients with and without suspected infection. Journal of Critical Care. 2017; 38: 1–5. DOI: 10.1016/j.jcrc.2016.10.005.
  43. Jung Y.T., Lee J.G., Lee S.H., et al. Combination of QSOFA score with hyperlactatemia improves mortality prediction for surgical patients. Critical Care Medicine. 2018; 46(1): 715. DOI: 10.1097/01.ccm.0000529464.06958.86.
  44. Song J.U., Sin C.K., Park H.K., et al. Performance of the quick Sequential (sepsis-related) Organ Failure Assessment score as a prognostic tool in infected patients outside the intensive care unit: a systematic review and meta-analysis. Critical Care. 2018; 22(1): 28. DOI: 10.1186/s13054-018-1952-x.
  45. Maitra S., Som A., Bhattacharjee S. Accuracy of quick Sequential Organ Failure Assessment (qSOFA) score and systemic inflammatory response syndrome (SIRS) criteria for predicting mortality in hospitalized patients with suspected infection: A meta-analysis of observational studies. Clinical Microbiology and Infection. 2018; 24(11): 1123–1129. DOI: 10.1016/j.cmi.2018.03.032.
  46. Barreto B., Luz M., Gusmao-Flores D. Prognostic accurancy of quick sequential organ failure assessment (qSOFA) score for mortality: systematic review and meta-analysis. Critical Care. 2018; 22(S1): 34. DOI: 10.1186/s13054-018-1973-5.
  47. Fernando S.M., Tran A., Taljaard M., et al. Prognostic accuracy of the quick sequential organ failure assessment for mortality in patients with suspected infection. Annals of Internal Medicine. 2018; 168(4): 266–275. DOI:10.7326/M17–2820.

 

Whether free hemoglobin can be a severity’s marker of general condition of the patient with sepsis?

Y.P. Orlov1, 3, V.T. Dolgikh2, A.V. Glushchenko3

1 The Department of Anesthesiology and Intensive Care, Federal state budgetary educational institution higher education “Omsk State Medical University” Ministry of Health of Russian Federation, Omsk

2 The Department of Pathophysiology with course of clinical pathophysiology, Federal state budget educational institution higher education “Omsk State Medical University” Ministry of Health of Russian Federation, Omsk

3 BUZOO “City clinical emergency hospital N 1», Omsk, Russia

For correspondence: Orlov Yuriy Petrovich — MD, Professor of Anesthesiology and reanimatology, Russian “Omsk State Medical University” the Ministry of health of Russia; e-mail: orlov-up@mail.ru

For citation: Orlov YP, Dolgikh VT, Glushchenko AV. Whether Free Hemoglobin can be a Severity’s Marker of General Condition of the Patient with Sepsis? Alexander Saltanov Intensive Care Herald. 2018;1:48–54.

DOI: 10.21320/1818-474X-2018-1-48-54


Purpose of Research: to determine whether we can use free hemoglobin concentration as early prognostic marker and a predictor of mortality in sepsis. Materials and Methods. In a retrospective study in 60 patients aged 47,6 ± 7,2 years with sepsis (30,4 ± 2,1 points on the Mannheim’s scale for evaluation of the severity of peritonitis) modern methods of statistics (ROC-analysis) hypothesis was tested, whether level of free hemoglobin in the first 24 hours from the moment of admission can be used as a biomarker for diagnosis and prognosis for severe sepsis. Informative criterion was compared with the information of the procalcitonin test. Results. The present study had shown that the above average free hemoglobin concentration, measured on the first day of the heavy flow of sepsis, is directly connected with increased 30-days mortality, and the level of free hemoglobin in a first day of the disease has high sensitivity, specificity, and can determine the outcome of sepsis with accuracy up to 96,7 %. Conclusion. Free hemoglobin concentration above medium size identified on the first day of the currents of severe sepsis, is directly related to increased 30-day mortality, and researched level of free hemoglobin in day 1 of the disease has a high proportion of sensitivity and specificity. Level of free hemoglobin is Predictor outcome of sepsis in the first 24 hours after the start of therapy, but the results did not rule out the need to use the necessary test from septic patients, but rather the feasibility of combining the two dictates the criteria to assess the outcome of severe septic process that requires further research.

Keywords: free hemoglobin, procalcitonin, sepsis, ROC-analysis

Received: 15.01.2018


References

  1. Weis S., Carlos A.R., Moita M.R., et al. Metabolic Adaptation Establishes Disease Tolerance to Sepsis. Cell. 2017; 169(7): 1263–1275. e14. doi: 10.1016/j.cell.2017.05.031.
  2. Harbarth S., Holeckova K., Froidevaux C., et al. Geneva Sepsis Network. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am. J. Respir. Crit. Care Med. 2001; 164(3): 396–402.
  3. Selberg O., Hecker H., Martin M., et al. Discrimination of sepsis and systemic inflammatory response syndrome by determination of circulating plasma concentrations of procalcitonin, protein complement 3a, and interleukin-6. Crit. Care Med. 2000; 28(8): 2793–2798.
  4. Yu X., Ma X., Ai Y. Diagnostic value of serum procalcitonin for infection in the immunocompromised critically ill patients with suspected infection. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2015; 27(6): 477–483. doi: 10.3760/cma.j.issn.2095-4352.2015.06.012.
  5. Jordi Rello J., Francisco Valenzuela-Sánchez F., Ruiz-Rodriguez M., Moyano S. Sepsis: A Review of Advances in Management. Adv. Ther. 2017; 34(11): 2393–2411. doi: 10.1007/s12325-017-0622-8.
  6. Мчедлишвили Г.И. Гемореология в системе микроциркуляции: ее специфика и практическое значение. Тромбоз, гемостаз иреология. 2002; 4(12); 18–24. [Mchedlishvili G.I. Hemorheology in microcirculation system: its specificity and practical significance. Thrombosis, hemostasis and rheology. 2002; 4(12); 18–24. (In Russ)]
  7. Сторожук П.Г. Ферменты прямой и косвенной антирадикальной защиты эритроцитов и их роль в инициации процессов оксигенации гемоглобина, антибактериальной защите и делении клеток. Вестн. инт. терапии. 2000; 3: 8–13. [Storozhuk P.G. Enzymes direct and indirect antiradical protect red blood cells and their role in triggering processes of oxygenation of hemoglobin, antibacterial protection and cell division. Vestn. intensive therapy. 2000; 3: 8–13. (In Russ)]
  8. Huffman D.L., Bischof L.J., Griffitts J.S., Aroian R.V. Pore worms: using Caenorhabditis elegans to study how bacterial toxins interact with their target host. Int. J. Med. Microbiol. 2004; 293: 599–607. doi: 10.1078/1438-4221-00303.
  9. Aroian R., van der Goot F.G. Pore-forming toxins and cellular nonimmune defenses (CNIDs) Curr. Opin. Microbiol. 2007; 10: 57–61. doi: 10.1016/j.mib.2006.12.008.
  10. Gonzalez M.R., Bischofberger M., Pernot L., et al. Bacterial pore-forming toxins: the (w)hole story? Cell. Mol. Life Sci. 2008; 65: 493–507. doi: 10.1007/s00018-007-7434-y.
  11. Bull B.S., Kuhn I.N. The production of schistocytes by fibrin strands (a scanning electron microscope study). Blood. 1970; 35: 104–111.
  12. Heyes H., Köhle W., Slijepcevic B. The appearance of schistocytes in the peripheral blood in correlation to the degree of disseminated intravascular coagulation. An experimental study in rats. Haemostasis. 1976; 5: 66–73.
  13. Ehrnthaller C., Ignatius A., Gebhard F., Huber-Lang M. New insights of an old defense system: structure, function, and clinical relevance of the complement system. Mol. Med. 2011; 17: 317–329.
  14. Pöschl J.M., Leray C., Ruef P., et al. Endotoxin binding to erythrocyte membrane and erythrocyte deformability in human sepsis and in vitro. Crit. Care Med. 2003; 31: 924–928. doi: 10.1097/01.CCM.0000055366.24147.80.
  15. Lang F., Gulbins E., Lang P.A., et al. Ceramide in suicidal death of erythrocytes. Cell Physiol. Biochem. 2010; 26: 21–28. doi: 10.1159/000315102.
  16. Lang F., Qadri S.M. Mechanisms and Significance of Eryptosis, the Suicidal Death of Erythrocytes. Blood Purif. 2012; 33: 125–130. doi: 10.1159/000334163.
  17. Hod E.A., Zhang N., Sokol S.A., et al. Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation. Blood. 2010; 115: 4284–4292. doi: 10.1182/blood-2009-10-245001.
  18. Dutra F.F., Bozza M.T. Heme on innate immunity and inflammation. Front. Pharmacol. 2014; 5: 115. doi: 10.3389/fphar.2014.00115.
  19. Vinchi F., Tolosano E. Therapeutic approaches to limit hemolysis-driven endothelial dysfunction: scavenging free heme to preserve vasculature homeostasis. Oxid. Med. Cell. Longev. 2013; 2013: 396527. doi: 10.1155/2013/396527.
  20. Linder M.M., Wacha H., Feldmann U., et al. The Mannheim peritonitis index. An instrument for the intraoperative prognosis of peritonitis. Chirurg. 1987; 58(2): 84–92.
  21. Singer M., Deutschman C.S., Seymour C.W., et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8): 801–810. doi: 10.1001/jama.2016.0287.
  22. Vincent J.L., Ince C., Bakker J. Clinical review: Circulatory shock-an update: a tribute to Professor Max Harry Weil. Crit. Care. 2012; 16(6): 239. doi: 10.1186/cc11510.
  23. Савельев О.Н., Сухоруков В.П., Киселева А.В. Определение свободного гемоглобина плазмы крови гемоглобинцианидным методом. Лаб. дело. 1990; 10: 45–47. [Savelyev O.N., Sukhorukov V.P., Kiseleva A.V. Definition of free plasma hemoglobin gemoglobincianidnym method. Lab. case. 1990; 10: 45–47. (In Russ)]
  24. Мeisner M. PCT — procalcitonin. A new and innovative parameter in diagnosis of infections. Berlin: BRAHMS Diagnostica, 1996.
  25. Belcher J.D., Mahaseth H., Welch T.E., et al. Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice. American Journal of Physiology. 2005; 288(6): 2715–2725. doi: 10.1152/ajpheart.00986.2004.
  26. Belcher J.D., Mahaseth H., Welch T.E., et al. Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice. Journal of Clinical Investigation. 2006; 116(3): 808–816. doi: 10.1172/JCI26857.
  27. Jeney V., Balla J., Yachie A., et al. Pro-oxidant and cytotoxic effects of circulating heme. Blood. 2002; 100(3): 879–887.
  28. Kumar S., Bandyopadhyay U. Free heme toxicity and its detoxification systems in human. Toxicology Letters. 2005; 157(3): 175–188. doi: 10.1016/j.toxlet.2005.03.004.
  29. Weinberg E.D. Iron and infection. Microbiol. Rev. 1978; 42(1): 45–66.
  30. Cassat J.E., Skaar E.P. Iron in Infection and Immunity. Cell. Host. Microbe. 2013; 13(5): 509–519. doi: 10.1016/j.chom.2013.04.010.
  31. Brauckmann S., Effenberger-Neidnicht K., de Groot H., et al. Lipopolysaccharide-induced hemolysis: Evidence for direct membrane interactions. Sci.Rep. 2016; 6: 35508. doi: 10.1038/srep35508.